HPK1 (hematopoietic progenitor kinase 1) is a MAP4K family kinase that negatively regulates T cells, B cells, and dendritic cells. HPK1 kinase-dead knock-in mice demonstrate increased CD8+ T cell function, increased cytokine secretion, and robust anti-tumor immune responses, making HPK1 an attractive high-priority target in immuno-oncology.

We are currently in a multicenter, open-label Phase 1/2 trial (NCT05128487) with NDI-101150 as monotherapy and in combination with pembrolizumab for the treatment of adults with advanced solid tumors. NDI-101150 is a reversible, ATP-competitive HPK1 inhibitor with features distinct from anti-programmed cell death protein 1 (PD1) checkpoint inhibitors. It was designed using a comprehensive approach combining structural biology, physics-based computational chemistry, and medicinal chemistry and is highly potent and highly selective over other MAPK4 and immune receptor kinases. Preclinical data show NDI-101150 enhances the activation of T cells, B cells, and dendritic cells, resulting in a robust anti-tumor immune response, even under immunosuppressive conditions. Clinical data indicate NDI-101150 achieves robust target engagement and enhances infiltration of T and dendritic cells into tumors, supporting the proposed mechanism of action. Treatment with NDI-101150 monotherapy in clinical trials has demonstrated an acceptable safety profile and preliminary evidence of clinical benefit in patients.

WRN (Werner syndrome helicase) is required for DNA replication and DNA repair. Multiple groups have shown via CRISPR screening that tumors with microsatellite instability (MSI) have defective mismatch repair and are absolutely dependent on WRN helicase activity for survival. A WRN inhibitor is a validated targeted approach in the arsenal to treat MSI tumors, which are screened for in the clinic using established assays. MSI-high tumors are present across lineages, and are more highly prevalent in colorectal, gastric, and endometrial cancers.

We have identified potent and selective WRN inhibitor clinical candidates with best-in-class potential that show complete and durable target engagement in vivo, which results in tumor regressions of MSI-high xenograft tumors. Our preclinical data suggests that the high potency of our WRN development candidates provides the opportunity for greater target engagement at a lower dose, leading to the potential for improved efficacy and tolerability.

The family of SIKs (salt-inducible kinases) are involved in regulation of transcriptional programs that activate pathological processes such as pro-inflammatory signals and inhibit repair mechanisms. SIK inhibitors are thus expected to correct these imbalances by interrupting pathological pathways and permitting repair.

SIK inhibitors offer potential differentiation from current treatments by attenuating tissue destruction and promoting the resolution of pathology. The biological roles of the SIKs are complex. We are designing SIK inhibitors with precise selectivity profiles and characterizing their pharmacology to target specific disease states.

cGAS (cyclic GMP-AMP synthase) is a component of the innate immune system that senses cytosolic dsDNA and initiates an inflammatory cascade. It is a key driver of inflammation in autoimmune and other diseases. cGAS activates the protein STING (stimulator of interferon genes), which propagates a pro-inflammatory response culminating in the activation of the type I interferon and NF-kB pathways.

We are currently designing potent, selective cGAS inhibitors that exploit the natural dynamics of the binding pocket through structure enablement and computational chemistry to suppress pathological activation and thus treat immune-mediated inflammatory disorders.

AMPK (AMP-activated protein kinase) is a kinase that serves as a critical regulator of energy-sensing and metabolic homeostasis in many tissues. Activation of AMPK in the body has broad impact across liver, skeletal muscle, kidney, and other tissues. Small molecule activation of AMPK has long been recognized as a potential strategy to treat metabolic disorders.

AMPK is a heterotrimer comprised of α, β and γ subunits; two β isoforms exist. We are using structural biology combined with computational chemistry approaches to identify isoform-selective, small molecule activators of AMPK heterotrimers. Isoform-selective activators of AMPK have the potential to modulate cellular energetics and metabolic homeostasis in different tissues to treat metabolic disorders, such as diabetes, diabetic nephropathy, and metabolic dysfunction-associated steatohepatitis (MASH). In 2022, Nimbus and Eli Lilly and Company entered into a research collaboration and exclusive worldwide license agreement for the development and commercialization of novel targeted therapies that activate a specific isoform of AMPK for the treatment of metabolic diseases. Nimbus is responsible for research activities and Lilly will be responsible for development and commercialization activities worldwide. Learn more >

ACC (acetyl-CoA carboxylase) is an enzyme involved in de novo lipogenesis (the synthesis of endogenous fatty acids) and the regulation of beta-oxidation (the process by which fatty acids are broken down at a cellular level). Nimbus developed ACC inhibitors, including NDI-010976, a potent, liver-targeted allosteric inhibitor for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) and potentially hepatocellular carcinoma and other diseases. In 2016, Gilead acquired our ACC inhibitor program and is currently conducting Phase 2 studies for the treatment of MASH.

TYK2 (tyrosine kinase 2) is an important signal-transducing kinase implicated in immune-mediated diseases. We discovered and developed highly selective allosteric TYK2 inhibitors, including NDI-034858, which we evaluated in Phase 2 studies in moderate-to-severe psoriasis and psoriatic arthritis. Both preclinical and clinical data demonstrate the molecule’s best-in-class potential. In 2023, Takeda acquired our TYK2 program and is currently conducting multiple Phase 2/3 studies.